The present invention relates to a process for preparing the inhalation anesthetic 1,2,2,2-tetrafluoroethyl difluoromethyl ether (also known as desflurane).
Desflurane is one of the most effective and widely used inhalation anesthetics currently available on the market. As such, there is considerable interest in developing improved synthetic routes that are practical to implement on commercial scales. One commercial process for the synthesis of desflurane disclosed in U.S. Pat. No. 5,026,924, herein incorporated by reference, relates to a process for preparing desflurane from the intermediate isoflurane, (1-chloro-2,2,2-trifluoroethyl difluoromethyl ether) by treatment with hydrogen fluoride in the presence of antimony pentachloride, alone or in combination with antimony trichloride according to reaction (1).
CF3CHClOCHF2+HF+SbCl5(cat.)xe2x86x92CF3CHFOCHF2+HClxe2x80x83xe2x80x83(1)
While reaction (1) serves as a basis for a successful commercial route for desflurane, a drawback associated with its use is the generation of by-products in addition to desflurane. A major proportion of these by-products is bis-1,2,2,2-tetrafluoroethyl ether, whose formation is undesirable in at least two aspects. In one aspect, the formation of this by-product is achieved at the expense of isoflurane consumed and desflurane produced. The formation of the by-product therefore lowers the overall recovery of the reaction. In a second aspect, the formation of the by-product also increases the complexity of the subsequent purification of desflurane. Bis-1,2,2,2-tetrafluoroethyl ether exists as a mixture of two stereoisomers whose boiling points (37xc2x0 C. and 49xc2x0 C.) are similar to those of desflurane (b.p. 23.5xc2x0 C.) and isoflurane (b.p. 48.5xc2x0 C.) and therefore, multiple distillations stages are almost invariably needed to separate the two stereoisomers of this impurity from useful materials. Moreover, distillation fractions containing the by-products often contain substantial quantities (e.g.,  greater than 99 percent by weight) of desflurane. Due to the fact that additional separations of the contaminated fractions are unfavorable from the standpoint of economics, these fractions are typically discarded, lowering the isolated yield of the purified desflurane product. Accordingly, it is advantageous to adjust the reaction conditions for reaction (1) to minimize the levels of by-products present in the crude reaction product.
Further optimization of processes based on reaction (1) is also desirable from the standpoint of reducing the levels of hazardous waste streams that are associated with the process. For example, minimizing the quantity of antimony pentachloride that is used decreases the associated volume of water containing the spent catalyst, as aqueous waste streams containing antimony salts are burdensome to treat and costly to dispose of.
Accordingly, alternative cost-effective and efficient methods of preparing desflurane based on reaction (1) are needed. In addition, these methods are preferably more favorable from the standpoint of reduced volumes of hazardous waste streams and reduced environmental impact.
In one embodiment, the invention relates to a method for the preparation of desflurane wherein isoflurane is reacted with 0.7-1.2 mol. % of antimony pentachloride and 1.3-2.2 molar equivalents of hydrogen fluoride. Typically, the method is conducted by addition of hydrogen fluoride to a mixture of isoflurane and antimony pentachloride. After the addition of hydrogen fluoride is completed, the reaction is preferably maintained at temperatures of about 9-18xc2x0 C. for about 6 to 7 hours, before being quenched.